p27(Kip1) deficiency promotes prostate carcinogenesis but does not affect the efficacy of retinoids in suppressing the neoplastic process.

p27 is a cell cycle suppressor gene, whose protein is a negative regulator of cyclin/cdk complexes. p27 is also a potential target of retinoids in cancer prevention studies. In benign prostate hyperplasia (BPH), and in most carcinomas, p27(Kip1) is down-regulated, suggesting its potential resistance to retinoids. To test this hypothesis, we examined the efficacy of 9-cis retinoic acid (9cRA) to suppress prostate cell proliferation (PECP) and carcinogenesis in p27(Kip1) deficient mice.
p27(Kip1) deficient (-/-), heterozygous (+/-) and homozygous (+/+) mice were treated for 7 days with testosterone, 9cRA, or with both, and cell proliferation in dorsolateral prostate (DLP) was determined by BrdU labeling. Prostate carcinogenesis was induced by N-Methyl-N-Nitrosourea (MNU) and hormone stimulation.
PECP in DLP of two-month-old mice of all genotypes was similar but significantly increased in old p27-/- mice only. Testosterone treatment increased PECP in all three p27 genotypes with the highest values in p27-/- mice. p27(Kip1) deficiency did not affect the response of PEC to 9cRA and to 9cRA+testosterone. The decrease of p27(Kip1) in p27+/- and p27-/- mice progressively increased the incidence and frequency of PIN and tumors. 9cRA suppressed PIN in all three p27 genotypes and this was associated with decreased PECP and increased cellular senescence.
This data indicates that p27(Kip1) deficiency promotes prostate cell proliferation and carcinogenesis but does not affect 9cRA's potential to suppress prostate carcinogenesis, suggesting that patients with PIN and carcinomas lacking or having a low level of p27(Kip1) expression may also benefit from clinical trials with retinoids.
AuthorsWinna Taylor, Amanda Mathias, Arshia Ali, Hengning Ke, Nikolay Stoynev, Anne Shilkaitis, Albert Green, Hiroaki Kiyokawa, Konstantin Christov
JournalBMC cancer (BMC Cancer) Vol. 10 Pg. 541 ( 2010) ISSN: 1471-2407 [Electronic] England
PMID20932324 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Antineoplastic Agents
  • Cdkn1b protein, mouse
  • Retinoids
  • Cyclin-Dependent Kinase Inhibitor p27
  • alitretinoin
  • Tretinoin
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Cell Cycle
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p27 (genetics, physiology)
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic
  • Genotype
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Prostatic Neoplasms (genetics)
  • Retinoids (metabolism)
  • Tretinoin (pharmacology)

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